The study of genetic lesions such as tumor-associated deletions has led to the identification of a number of tumor-suppressor genes which, if deleted or mutated, relieve the cell from negative growth control (Ponder, Nature 335:400 (1988); Stanbridge, Annu. Rev. Genet. 24:615 (1990); Lasko et al, Annu. Rev. Genet. 25:281 (1991); Marshall, Cell 64:313 (1991)). An inactivating mutation in one allele of a tumor suppressor gene is recessive, but becomes evident when the other allele is lost. This second event is often signified by loss of heterozygosity (LOH) at polymorphic DNA marker loci in or near the gene. LOH in human hepatocellular carcinomas (HCCs) has been observed on a number of chromosomal arms including 4q, 5q, 8p, 10q, 11p, 13q, 16q, 17p and 22q (Wang and Rogler, Cytogenet. Cell Genet. 48:72 (1988); Buetow et al, Proc. Natl. Acad. Sci. USA 86:8852 (1989); Tsuda et al, Proc. Natl. Acad. Sci. USA 87:6791 (1990); Zhang et al, Jpn. J. Cancer Res. 81:108 (1990); Fujimori et al, Cancer Res. 51:89 (1991); Walker et al, Cancer Res. 51:4367 (1991); Emi et al, Cancer Res. 52:5368 (1992); Nose et al, Cancer 72:355 (1993), Takahashi et al, Hepatology 17:794 (1993)).
Expression of the mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II) receptor is often significantly reduced in both rat (Jirtle et al, Carcinogenesis 15:1473 (1994)) and human (Sue et al, Ann. Surgery, 222:171 (1995)) HCCs. The M6P/IGF-II receptor possesses distinct binding regions for both phosphomannosyl residues and IGFII (MacDonald et al, Science 239:1134 (1988); Kornfeld, Annu. Rev. Biochem. 61:307 (1992)). Primary functions of the M6P/IGF-II receptor include the trafficking of newly synthesized lysosomal enzymes from the Golgi to the lysosomes, and the endocytosis of extracellular lysosomal enzymes (Dahms et al, J. Biol. Chem. 264:12115 (1989)). However, apart from IGFII, secreted growth factors like proliferin (Lee and Nathans, J. Biol. Chem. 263:3521 (1988)) and the latent complex of TGF.beta.1 (Purchio et al, J. Biol. Chem. 263:14211 (1988); Kovacina et al, Biochem. Biophys. Res. Commun. 160:393 (1989)) also bind to the M6P/IGF-II receptor. Although binding of these growth factors to the M6P/IGF-II receptor will lead to their internalization and subsequent degradation in the lysosomes, the extracellular activation of TGF.beta.1 by plasmin is also greatly facilitated by the binding of the TGF.beta. latent complex to this receptor (Dennis and Rifkin, Proc. Natl. Acad. Sci. USA 88:580 (1991), Le Bleser et al, Hepatology 21:1429 (1995)), Kojima et al, J. Cell Biol. 121:439 (1993)). The M6P/IGF-II receptor is therefore required for both the activation of the growth inhibitor, TGF.beta.1 (Dennis and Rifkin, Proc. Natl. Acad. Sci. USA 88:580 (1991)) and the degradation of the mitogen, IGFII (Morgan et al, Nature 329:301 (1987); Kornfeld, Annu. Rev. Biochem. 61:307 (1992)). Consequently, the M6P/IGF-II receptor also plays an important role in negative cell growth control.
LOH at the M6P/IGF-II receptor locus in HCCs was recently reported (DeSouza et al, Oncogene 10:1725 (1995)). The presence of LOH in adenomas was also described, suggesting that allelic loss may be an early event in the etiology of hepatocellular tumors.